Cyclophilin A (CyPA) is a ubiquitous and highly conserved protein with peptidyl prolyl isomerase activity that widely expressed in eukaryotic and prokaryotic organisms. Initially, research suggested that CyPA functions as an intracellular protein molecule. Recently, more and more studies have found that intracellular cyclophilin A (iCyPA) can be secreted extracellularly in an autocrine or paracrine pathway to participate the signaling pathways mediated by the CD147 receptor to play a unique biological role when the body is under pathological conditions such as hypoxia, infection, and oxidative stress. This review mainly introduces the recent study of extracellular cyclophilin A (eCyPA) and the main receptor CD147-mediated biological activity pathway, and hopes to better provide eCyPA as a new point of diagnosis and treatment for related diseases.